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Managing Broken Genes in the Age of Genomics

Managing Broken Genes in the Age of Genomics. Jared E. Decker State Beef Genetics Specialist DeckerJE@missouri.edu http://web.missouri.edu/~ deckerje/extension http://steakgenomics.blogspot.com/ https:// www.facebook.com/SteakGenomics. Broken Genes….

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Managing Broken Genes in the Age of Genomics

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  1. Managing Broken Genes in the Age of Genomics Jared E. Decker State Beef Genetics Specialist DeckerJE@missouri.edu http://web.missouri.edu/~deckerje/extension http://steakgenomics.blogspot.com/ https://www.facebook.com/SteakGenomics

  2. Broken Genes… • ~100 genes where one copy is functional and the other is broken • ~20 genes where the broken copy is a lethal mutation • Called Loss of Function mutations Science Vol. 335 no. 6070 pp. 823-828 DOI: 10.1126/science.1215040

  3. Broken Genes… Inconvenient Genetic Truth • Everybody has genetic defects!!! Even the most beautiful people in the world

  4. Broken Genes… Inconvenient Genetic Truth • Everybody has genetic defects!!! Even the most caring people in the world

  5. Broken Genes…

  6. Broken Genes… What happens when a broken gene is inherited from the father and the mother? • Genetic abnormality • Spontaneous abortion

  7. Broken Genes…

  8. Broken Genes in Dogs Causal mutations identified at Mizzou by whole genome sequencing

  9. Broken Genes in Dogs A documented human disease corresponds to each of the canine diseases caused by mutations identified by whole genome sequencing

  10. Broken Genes in Cats Mutations found by Lyons Cat Genetics lab

  11. 99 Lives Cat Genome Initiative • Full genome sequence 99 cats • Centralized and publically available • Any breed or population of cat worldwide • Interesting trait or health issue • 12 cats races • 24 major breeds • Rare breeds • Other felids

  12. Broken Genes… What happens when a broken gene is inherited from the sire and the dam? • Genetic abnormality • Spontaneous abortion

  13. Broken Genes… • Some we know about • Some we don’t KNOWN Even the most beautiful cattle in the world

  14. Silver Lining

  15. Silver Lining • DNA tests can now be developed in a few months • With DNA tests available, frequency of the known genetic defect rapidly decreases • Now we can manage genetic defects

  16. Genetic Defects • There are more than 35 genetic defects in cattle with a DNA test

  17. Tibialhemimelia (TH) • Documented in 1950’s • Became prevalent in 2000’s due to heterozygotes having straight hind limbs and long shaggy hair • Present in Galloway, Shorthorn, %Maine-Anjou, %Chianina, and other breeds with open herd books • Single autosomal recessive Beever, Jonathan Edward, and Brandy Michele Marron. "Screening for the genetic defect causing tibial hemimelia in bovines." U.S. Patent 8,158,356, issued April 17, 2012.

  18. Tibialhemimelia (TH) • Due to ~46,000 bp deletion in ALX homeobox4 (ALX4) gene, a transcription factor expressed in developing bones, limbs, hair, teeth, and mammary tissue. • “Note the twisted hind limbs and the large abdominal hernia. The calf also had a meningocele and cryptorchidism.” (Whitlock, Kaiser, and Maxwell, 2008) Beever, Jonathan Edward, and Brandy Michele Marron. "Screening for the genetic defect causing tibial hemimelia in bovines." U.S. Patent 8,158,356, issued April 17, 2012.

  19. Pulmonary Hypoplasia with Anasarca (PHA) • Present in Maine-Anjou, %Chianina, and Shorthorn • Lethal autosomal recessive • “Note the severe anasarca.” (Whitlock, Kaiser, and Maxwell, 2008)

  20. Bovine Arthrogryposis Multiplex Congenita (AM) • Also known as “curly calf” • Recognized by American Angus Association as a genetic defect on September 16, 2008. • Recessive mutation • Twisted spin, contracted legs, light muscled

  21. Neuropathic Hydrocephalus (NH) • Recognized by American Angus Association as a genetic defect on June 12, 2009. • Recessive mutation • Calves carried to near term • Weigh 25 to 35 lbs • Head is severely enlarged • Bones of skull are malformed • No brain tissue is present and skull is filled with fluid

  22. Idiopathic Epilepsy (IE) • In Hereford cattle • Autosomal recessive • Calves experience seizures, especially during stress such as temperature or handling

  23. Osteopetrosis (OP) • Also known as “Marble Bone Disease” • In Red Angus • Cattle are typically born dead or die in first 24 hours • Bones are extremely brittle and lower jaw is short • ~2721 bpdeletion in the SLC4A2gene affecting exons 2 and 3

  24. Congenital Hypotrichosis (HY) • In Hereford cattle • Autosomal recessive • 8 base pair deletion mutation in first exon of the keratin 71 (KRT71) gene • Complete or partial loss of hair

  25. Contractual Arachnodactyly (CA) • Also known as “Fawn Calf” • Nonlethal recessive genetic abnormality • Upper limb joints have a reduced range of motion

  26. Developmental Duplications(DD) • Polymelia • Most die as embryos

  27. The Truth The Truth: Every Living Thing Is A Genetic Defect Carrier

  28. What to do before breeding Seedstock: • Test at-risk breeding stock for genetic defects • Do we know the pedigree of the animals? • Are there carriers in the pedigree?

  29. What to do before breeding Commercial: • Crossbred • Outcross • Avoid using the same bloodlines • Test at-risk breeding stock for genetic defects • Do we know the pedigree of the animals? • Are there carriers in the pedigree?

  30. What to Do with an Abnormal Calf • Create a documented record of what happened • Take a picture or video of affected calves • Freeze the entire animal if possible, otherwise preserve the abnormal body part • Obtain 40 hair bulbs from the calf, dam, and sire

  31. What to Do with an Abnormal Calf • Breeders should contact their breed association and local veterinarian • Need intensive description of phenotype • The majority of abnormalities are caused by the environment, not genetics

  32. Broken Genes… What happens when a broken gene is inherited from the sire and the dam? • Genetic abnormality • Spontaneous abortion

  33. Variants Reducing Fertility • Sequence the genomes of 165 registered bulls • We will discover hundreds of broken genes • Most embryonic lethals • Breeds co-sponsoring sequencing:

  34. Variants Reducing Fertility • Sequencing completed for all 165 of the animals • Currently running data thru analysis pipeline

  35. Variants reducing Fertility • We have already analyzed the genomes of 11 bulls

  36. Variants reducing Fertility • We have already analyzed the genomes of 11 bulls • Identified 176 possibly lethal alleles

  37. Validation

  38. Validation

  39. Genomic Prediction • Predictions are sums of marker effects • For lethal mutations • Homozygous normal: effect is 0 • Heterozygous lethal: effect is -qif • Allows publication of a fertility EPD

  40. Mate Selection Software • Avoid mating carriers of the same lethal mutation • Will also manage • Genetic merit • Genetic diversity • Built upon economic selection indexes

  41. The Old Paradigm • See abnormal calf • Bury calf

  42. The Current Paradigm • Report abnormal calves • Collect data • Create a test • Manage the defect

  43. The Genomics Paradigm? • Sequence influential AI sires • Create tests for LOF mutations • Manage the mutations while accounting for overall genetic merit

  44. Optimal practices

  45. Thank You! Questions? http://web.missouri.edu/~deckerje/extension http://steakgenomics.blogspot.com/ https://www.facebook.com/SteakGenomics

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